Toen,in 1953,de structuur van DNA ontrafeld werd door J.D.Watson en F.Crick (zie Bericht,Blog/De dubbele helix) en kort daarna de code van deze belangrijke molecule bekend werd,begon de stormachtige ontwikkeling van de moleculaire biologie.Zeer snel werd het centraal dogma ervan voorgesteld en aanvaard,vooral onder impuls van Francis Crick.Volgens dit dogma ging het als volgt : DNA/RNA/PROTEÏNE.Het duurde echter niet lang om in te zien dat dit dogma nogal simplistisch was.De weg van DNA naar proteïne was wel ingewikkelder dan eerst gedacht.Er komen tal van aspecten bij kijken tussen DNA en de uiteindelijke proteïnen.
2-DEFINITIE.
De laatste jaren is het aantal informaties over epigenetica gestaag toegenomen en men kan er zich aan verwachten dat dit in de 21e eeuw nog aan belang zal winnen.Het is ook niet moeilijk een definitie te vinden voor deze actuele tak van de moleculaire biologie.Volgens Microsoft Encarta-Winkler Prins 2007 is in de genetica een epigenetische verandering een fenotypische verandering ten gevolge van variabele genexpressies zonder dat daarbij sprake is van een verandering van het genotype.Uit de weelde aan teksten over "epigenetica" is "Epigenetic:The science of change." zeker aangewezen om klaarheid in de begrippen te scheppen. www.ehponline.org
-"The word "epigenetic" literally means...in addition to changes in genetic sequences...The term has involved to include any process that alters gene activity without changing the DNA sequence and leads to modifications that can be transmitted to daughter cells-although experiments show that some epigenetic changes can be reversed-."
-"Epigenetic processes are natural and essential to many organism functions but,if they occur improperly,there can be major adverse health and behavioral effects."
3-MECHANISMEN.
Er bestaan talrijke epigenetische mechanismen om de expressie van de genen in DNA te beïnvloeden.Deze mechanismen berusten zowel op processen op het niveau van DNA zelf als op invloeden van het externe milieu.Vooraleer in te gaan op een beschrijving van diverse belangrijke mechanismen is het verhelderend het "lac operon" voor ogen te hebben (J.Monod,F.Jacob,A.Lwoff).
-"lac OPERON".
In het genome van talrijke organismen is er een gen verantwoordelijk voor de vorming van een messenger RNA (door transcriptie) die in het cytosol leidt tot de productie van een enzyme (proteïne),bv.galactosidase,vereist voor het metabolisme van lactose.Om RNA te vormen moet de expressie van het gen geactiveerd worden.Normalerwijze is er in het DNA een "repressor" aanwezig die de transcriptie blokkeert (de repressor is doorgaans een speciale proteïne).Om tot de vorming van galactosidase te komen moet deze repressor gedesactiveerd worden.Dit gebeurt in de aanwezigheid van lactose (dus een externe invloed op de expressie).Pas daarna kan lactose gemetaboliseerd worden.Als er geen lactose is treedt de repressor terug in actie.Dergelijke mechanisme bestaan ook voor andere facetten van de DNA expressie.Men heeft hier dus een duidelijk voorbeeld van een epigenetische verandering geïnduceerd door het externe milieu.
-EXTERNE MECHANISMEN.
DNA methylering en chromatine omvorming. Er zijn nog veel andere verschillende manieren om de regulering van de uitdrukking van de gene te komen (gen expressie).Een ervan is de omvorming van chromatine (het complex van DNA en histone proteïnen die zorgen voor de compacte vorm van DNA om in de celkern te kunnen geïntroduceerd worden).Deze omvorming kan optreden tijdens de modificatie van de aminozuren waaruit de histonen bestaan (posttranslatie modificatie) of door additie van methyl groepen aan het DNA op CpG siten (cytosine-fosfor-guanine) waardoor 5-methylcytosine ontstaat.De rol van methylering in de expressie van de genen kan niet voldoende als heel belangrijk bestempeld worden;Er zijn verschillende omvormingen van histonen bekend waaronder o.a. acetylering zeer belangrijk is.
-"Many types of epigenetic processes have been identified,they include methylation,acetylation,phosphorylation etc...Perhaps the best known epigenetic process is methylation,in part it is easiest to study with existing technology in DNA.This is the addition or removal of a methyl group (CH3),predominantly where cytosine bases occur consecutively.Another significant epigenetic process is chromatin modification.Chromatin is the complex of proteïns (histones) and DNA that is thightly bundled to fit into the nucleus.This modification alters the chromatin structure to influence gene expression.In general,tightly folded chromatin tends to be shut down or not expressed,while more open chromatin is functional or expressed."
-INTERNE DNA MECHANISMEN.
Mechansimen om de gen expressie te beïnvloeden doen ook beroep op elementen die via DNA gevormd werden.In het genome van alle organismen liggen,verspreid in de DNA moleculen,een groot aantal fragmenten die op eerste zicht niet coderen en die men lang als "junk" DNA beschouwde.Het feit dat ze sinds lang bestaan doet echter vermoeden dat ze wel een rol zouden kunnen spelen.De laatste jaren is het meer en meer duidelijk dat dit wel het geval is.Een aantal kleine RNA stukken kunnen ontstaan door transcriptie van delen van het "junk" DNA .Het gaat dan over verschillende micro RNA's waarvan bewezen werd dat ze belangrijk zijn voor de gen expressie.Een voorbeeld werd vermeld in het bericht over "Biotechnologie" waarin de werking van RNAi bij de bestrijding van een insecten plaag bij planten beschreven werd.Ook vanuit introns,stukken niet coderende DNA ingebed tussen de coderende exons van messenger RNA,kunnen dergelijke micro RNA's gevormd worden.De laatste jaren was interessante informatie te vinden in Scientific American.Representatieve uittreksels hiervan verduidelijken deze interne expressie mechanismen.
A/The unseen genome : gems among the junk.,W.Wayt Gibbs. Scientific American Nov.2003,p.47.
-"Just when scientists thought they had DNA almost figured out,they are discovering in chromosomes two vast,but largely hidden layers of information that affect inheritance,development and disease."
-"It will take years,perhaps decades,to construct a detailed theory that explains how DNA,RNA and the epigenetic machinery all fit into an interlocking,self-regulating system."
B/The unseen genome : beyond DNA.,W.Wayt Gibbs. Scientific American dec.2003,p.107.
-"DNA was once considered the sole repository of heritable information.But biologists are starting to decipher a separate,much more malleable layer of information encoded within the chromosomes.Genetics makes way for epigenetics."
-"The third part of the genomic machine ,as facinating as active RNA genes and probably even more important, is the "epigenetic" layer of information stored in the proteïns and chemicals that surround and stick to DNA.Epigenetic marks are so named because they can dramatically affect the health and characteristics of an organism- some are even passed from parent to child- yet they do not alter the underlying DNA sequence."
-"Special purpose enzymes take methyl molecules (groups !) derived from basic nutrients,such as folic acid and vitamin B12,and stick them onto certain C bases throughout the genome.In general,the more methylated a stretch of DNA,the less likely it is to be transcribed to RNA and to carry out its function.The silent allele of an imprinted gene is almost always highly methylated, for example.But imprinting may be a side job for DNA methylation;it mainly seems to defend the genome against parasite genetic elements called transposons."
C/Censors of the genome. N.C.Lau and D.P.Bartel.,Scientific American August 2003,p.34.
-"Biologists have been surprised to discover that most animal and plant cells contain a built-in system to silence individual genes by shredding the RNA they produce.Biotech companies are already working to exploit it."(shrredding=versnipperen).
-"Just within the past several years,scientists have discovered a more precise and more powerful security apparatus built into all plant and animal cells.Called RNA interference ,or RNAi,this system acts as a censor.When a threatening gene is expressed,the RNAi machinery silences it by intercepting and destroying only the offender's messenger RNA,without disturbing the messages of other genes."
-"When the RNAi machinery is not defending against attack,it apparently pitches in (aanbieden om te helpen) to help silence normal cellular genes during development transitions needed to form disparate cell types,such as neurons and muscle cells,or different organs,such as the brain and the heart." PS; Voor RNAi: zie ook www.answers.com/topic/rna-interference
D/Regulating evolution. S.B.Carroll,B.Prud'homme and N.Gompel. Scientific American, may 2008, p.60.
-"Switches within DNA that govern when and where genes are turned on enable genomes to generate the great diversity of animal forms from very similar sets of genes."
4-EVOLUTIE .(EPIGENETICA vs. LAMARCKISM/INPRINTING-IMPRINTING).
REFERENTIES.
www.hopkinsmedicine.org/press/2002/November/epigenetics.htm Backgrounder : Epigenetics and imprinted genes (a).
www.notes.utk.edu/bio www.the-scientist.com
Epigenetics :Genome,meet your environment. As the evidence accumulates for epigenetics,researchers reacquire a taste for Lamarckism. Leslie A.Pray,The Scientist,vol 18,Issue 13-14,july 5,2004.(b)
www.pi.csro.au Inheritance...more than just genes. (c)
UITTREKSELS.
-"There are different kinds of epigenetic " marks",chemical additions to the genetic sequence.The addition of methyl groups to the DNA backbone is used on some genes to distinguish the gene copy inherited from the father and that inherited from the mother.In this situation,known as "imprinting", the marks both distinguish the gene copies and tell the cell which copy to use to make proteïns."(a)
-"Imprinted genes don't rely on traditional laws of Mendelian genetics,which describe the inheritance of traits as either dominant or recessive.In Mendelian genetics,both parental copies are equally likely to contribute to the outcome.The impact of an imprinted gene copy,however,depends only on which parent it was inherited from.For some imprinted genes,the cell only uses the copy from the mother to make proteïns ,and others only that from the father." (a)
-"Researchers are still trying to understand the process by which cells maintain or change their gene's imprinting marks.In sperm and eggs for instance,imprinted gene copies have to be reimprinted."(a)
"Some findings suggest that pregnant mother's diet can affect her health in such a way that not only her children but her grandchildren (and possibly her great-grandchildren etc...)inherit the same health problems...Wouldn't that imply what every good biologist knows is practically scientific heresy : the Lamarckian inheritance of acquired characteristics?."(b) "In some instances the answer could be YES. (Agouti mice where environment interfaces with genomics)Epigenetic inheritance provides a rapid mechanism by which (an organism) can respond to the environment without having to change its hardware...It does give reason to consider long-refuted notions about the inheritance of acquired characteristics.Lamarck proposed that environmental cues could cause phenotype changes transmittable to offspring."(b)
N.B.Dit mag echter niet veralgemeend worden .Deze soort erfelijkheid is zeker gelimiteerd in de tijd en niet onderworpen aan Darwiniaanse selectie.Deze epigenetische erfelijkheid speelt zich meestal af op het niveau van de methylatie van DNA.De grote onopgeloste vraag blijft uit te leggen hoe deze omgevingseffecten zich vertalen in de gameten.(zie Blog/Evolutie-2-Jean Baptiste de Lamarck).
-"Although the study demonstrates that ,at least in mice, folic acid supplementation in pregnant mothers reduces the risk of their babies having certain health problems; the results cannot so far be extrapolated to humans."(b)
-"Epigenetics has always been Lamarckian.....Not that Mendelian genetics is wrong,far from it.The increased understanding of epigenetic change and the recent evidence indicating its role in inheritance and development doen't give epigenetics greater importance than DNA.Genetics and epigenetics go HAND IN HAND."(b)
-"A new wave oif research is unravelling the secret beyond genes to identify what other biological information parents pass to their offspring ,and cells pass on to each other when they divide.It seems that it is not just genes that are inherited from one generation to the next but other factors that particularly affect development and disease."(c)
5-ADDENDUM.
HUMAN EPIGENOME PROJECT (HEP).
"The Human Genome Project (HGP) provided the blueprint for life but the epigenome project (HEP) will tell us how this whole thing gets executed."
-"Epigenome is one is one of the many "omics" that is being talked about in the wake of the "Human Genome Project". The "Human Epigenome Project (HEP) was recently announced.The HGP provided the blueprint for life,but the epigenome will tell us how this whole thing gets executed,what determines when and where genes are switched on and off to produce a person."
-"For genetically identical twins differences can't be explained on the basis of pure genetics because the DNA is identical .Something else must be at play.That "something else" is chemical modification of genes that are heritable from one cell generation to the next and that affect gene expression but do not alter the DNA sequence....An epigenome is the description of these modifications across the whole genome;but unlike the genome DNA sequence ,each organism has multiple epigenomes - for example,in different cell types - that may change during its lifetime in response to environmental cues."
-"Epigenetics then,both at the level of unravelling mechanisms and mapping epigenomes and at the applied level,is an exciting area of research...It is one of the mainstream exciting areas of post-genomic biology." **************************************************************
ADDENDUM.
De epigenetica speelt een belangrijke rol in de ontwikkeling van levende organismen.Aan de oorsprong liggen processen die zowel op het niveau van DNA als onder invloed van de omgeving liggen.Deze trend wordt nu zeer algemeen erkend en het is daarom niet verwonderlijk dat de bekende ontwikkelings- en embryologie bioloog Scott F. Gilbert er een recent boek hierover uitgegeven heeft. "Ecological developmental biology".De inhoud van dit werk wordt als volgt samengevat:
-"Ecological development biology concerns the interactions between developing organisms and their environment contexts.It studies development in "the real world" of predators,competitors,symbionts, toxic compounds ,temperature changes and nutricial differences.The study of epigenetics -gene expression changes that are not caused by alterations of a gene's DNA sequence- has recently provided startling insights into the ways that these environmental factors can alter the phenotype of an organism.Epigenetic research has shown that such environmental influence are not only active but are also necessary for the normal development of most animal species.Ecological developmental biology also studies the pathological activities of environmental teratogens ,endocrine disruptors and certain diets.These findings offer new and unexpected insights for the understanding and treatment of diseases such as cancer,obesity and diabetes.In certain instances,such environmentally induced epigenetic states can be transmitted between generations ; this book final section attempts to describe what evolutionary theory might look like when it includes developmental plasticity,the epigenetic origin of novel phenotypes,the transmission of certain epigenetic traits between generations and the selection of relationships between hosts and a consortium of symbionts."
